Previous studies from this laboratory have led to the development of a nude mouse model system for the study of estrogen-dependent and estrogen-independent endometrial cancer. A series of transplantable endometrial carcinomas of differing histologic grade, steroid receptor status and sensitivities to hormones have been established and the principal investigator has described an "estrogen-like" effect of Tamoxifen (TAM) in this model system. Furthermore, a combination therapy regime utilizing TAM and medroxyprogesterone acetate (MPA) to inhibit endometrial cancer growth in the nude mouse has been developed and a unique feature of this system is that these tumors develop resistance to progestin (P) therapy analogous to that typically observed in humans with endometrial cancer. The proposed studies will utilize this model system to: 1) determine whether P-mediated tumor cell arrest involves the induction of apoptosis in endometrial cancer cells, 2) determine whether the development of resistance to P therapy involves the downregulation of progesterone (PR) or estrogen receptor (ER), 3) develop improved treatment strategies for inhibiting endometrial cancer growth by combination TAM/P therapy, and 4) to induce differentiation of poorly differentiated adenocarcinoma of the endometrium with retinoids and 5-azacytidine or by transfecting ER or PR into endometrial carcinoma cells as a means for restoring hormone sensitivity and improving response to endocrine therapy. It is suggested that biological principles derived from these studies will form the framework for drug treatment strategies for endometrial cancer.